Process for preparing quinolylacrylonitrile and intermediates therefor

ABSTRACT

3-[2-Cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile is prepared by reacting 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde with acetonitrile in the presence of a base and then adding a dehydrating to the reaction mixture to conduct dehydration. Under ordinary conditions, novel 3-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-hydroxypropionitrile is formed as an intermediate in the above reaction. Incidentally, when the above reaction is conducted in an organic solvent, 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-prop-2-enenitrile is directly formed.

TECHNICAL FIELD

The present invention relates to a process for preparing aquinolylacrylonitrile derivative from a quinolinecarbaldehydederivative. The quinolylacrylonitrile derivative produced by the methodof the invention is employable as a starting compound for thepreparation of a quinolylpropenal derivative which is utilizable for thesynthesis of a cholesterol reducing agent (HMG-CoA reductase inhibitor).

BACKGROUND ART

Until now, it has been known that the quinolylpropenal derivative isprepared by the two step process comprising a step of reducing aquinoline acrylate by diisobutylaluminum hydride to givequinolylpropenol and a subsequent step of oxidizing the quinolylpropenolby the use of a combination of oxalyl chloride and dimethylsulfoxide, ormanganese dioxide (J. Med. Chem., 34, 367 (1991)).

Further known is a method of selectively reducing the cyano group to aformyl group by the use of a diisobutylaluminum hydride reducing agent,keeping the double bond of an acrylonitrile compound to produce apropenal compound (Heterocycles, 29, 691(1989)).

Both of the above-mentioned process and method are disadvantageous fromthe viewpoint of industrial preparation because these process and methodutilize iisobutylaluminum hydride or manganese dioxide which requirescareful handling procedures and complicated post-treatment.

DISCLOSURE OF THE INVENTION

The present invention resides in a process for preparing3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-prop-2-enenitrile whichcomprises the steps of reacting2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde withacetonitrile in the presence of a base to produce a mixture of3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile and3-[2-cyclopropyl-4-(4-fluoro-phenyl)quinolin-3-yl]-3-hydroxypropionitrile;and dehydrating the mixture in the presence of a dehydrating agent.

The starting compound of the reaction of the invention, that is,2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde [hereinafterreferred to as quinolinecarbaldehyde derivative], the intermediateproduct, that is,3-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3-hydroxypropionitrile[hereinafter referred to as quinolylhydroxypropionitrile derivative],and the desired compound, that is,3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile[hereinafter referred to as quinolylacrylonitrile derivative] are thecompounds represented, respectively, by the following formulas (1), (2),and (3):

The invention further resides in the above-mentioned3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolin-3-yl]-3-hydroxypropionitrile.

The invention furthermore resides in a process for preparing3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinol-yl]prop-2-enenitrile whichcomprises the steps of reacting2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde withacetonitrile in the presence of a base; and dehydrating the resultingproduct in the presence of a dehydrating agent.

The invention furthermore resides in a method for preparing3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile whichcomprises reacting2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde withacetonitrile in an organic solvent in the presence of a base.

The quinolylacrylonitrile derivative of the formula (3) {i.e.,3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile}obtained by the invention can be converted into3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enal by reducingthe derivative using a Raney-nickel in the presence of a combination offormic acid and water [in an amount of 0.25 to 1 volume part per onevolume part of the formic acid].

DETAILED DESCRIPTION OF THE INVENTION

The 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde of theformula (1) which is the starting material of the reaction of theinvention is described in JP-A-1-279866, EP-A-304063, and U.S. Pat. No.5,011,930, and is already known.

Examples of the bases employed in the reaction of the invention includea metal hydride such as lithium hydride, sodium hydride, potassiumhydride, or calcium hydride; a metal amide such as lithium amide, sodiumamide, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, orpotassium bis(trimethylsilyl)amide; a metal alkoxide such as sodiummethoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide,magnesium methoxide, or magnesium ethoxide; an alkyl lithium such asmethyllithium, butyllithium, or t-butyllithium; or a metal hydroxidesuch as lithium hydroxide, sodium hydroxide, potassium hydroxide, orcalcium hydroxide. Preferred are a metal hydride, a metal alkoxide, anda metal hydroxide. More preferred are a metal hydride and a metalalkoxide.

The base is employed in an amount of preferably 0.9 to 3.0 moles, morepreferably 1.0 to 2.0 moles, per one mole of the starting compound,i.e., the quinolinecarbaldehyde derivative.

In the reaction, the acetonitrile is employed in an amount of preferably0.9 to 100 moles, more preferably 1.0 to 60 moles, per one mole of thestarting compound, i.e., the quinolinecarbaldehyde derivative.

In the reaction, the dehydrating agent functions to dehydrate thebelow-mentioned quinolylhydroxypropionitrile derivative having ahydroxyl group which is probably produced in the reaction as anintermediate product to give the desired product [quinolylacrylonitrilederivative having a double bond] according to the below-illustratedreaction (4):

Examples of the dehydrating agents include inorganic acids such ashydrochloric acid and sulfuric acid; organic acids such as formic acid,acetic acid, and trifluoroacetic acid; organic acid esters such asmethyl formate, ethyl formate, propyl formate, butyl formate, and ethylacetate; amides such as N,N-dimethylformamide; organic acid anhydridessuch as acetic anhydride and trifluoroacetic anhydride; acid chloridessuch as mesyl chloride, thionyl chloride, and acetyl chloride; tertiaryamines such as trimethylamine, triethylamine, ethyldiisopropylamine,diethylisopropylamine, and benzyldimethylamine; and silane compoundssuch as 1,1,1,3,3,3-hexamethyldisilazane. Preferred are organic acidesters and a combination of an acid chloride and a tertiary amine. Morepreferred are organic acid esters. Most preferred are formic acidesters. The dehydrating agent is employed in an amount of preferably 0.1to 100 moles, more preferably 0.2 to 50 moles per one mole of thestarting compound, i.e., the quinolinecarbaldehyde derivative.

The reaction of the invention can be carried out by reacting thequinolinecarbaldehyde derivative and acetonitrile in the presence of abase to produce a mixture of the quinolylhydroxypropionitrile derivative(intermediate product) and the quinolylacrylonitrile derivative (desiredproduct), and completing the reaction upon addition of a dehydratingagent at an atmospheric pressure or an increased pressure. The reactiontemperature is in the range of, preferably, −78° C. to 80° C., morepreferably −30° C. to 50° C.

The reaction of the starting compounds (guinolinecarbaldehyde derivativeand acetonitrile) in the presence of a base can be carried out in anorganic solvent to produce directly (this means “without utilizing adehydrating agent”) the desired product. The organic solvent is oneother than the acetonitrile.

The organic solvent preferably has a dielectric constant of 10 or lessin the temperature range of 20 to 25° C. (at an optionally selectedtemperature in this range). The details of “dielectric constant” aredescribed in “Chemistry Handbook, Basic Issue, 4th edition (II)”(Maruzen Publishing), and “Solvent Handbook, 1st edition” (KodanshaScientific). Examples of the organic solvents include aliphatic solventssuch as hexane, heptane, cyclohexane, methylene chloride, chloroform,and carbon tetrachloride; aromatic solvents such as benzene, toluene,xylene, chlorobenzene and dichlorobenzene; and ether solvents such asmethylal, tetrahydrofuran, and dioxane. Preferred are aromatic solventsand ether solvents. More preferred are aromatic solvents. Most preferredis toluene. The organic solvents can be employed singly or incombination.

The organic solvent can be employed in an amount of preferably 0.5 to 50weight parts, more preferably 1 to 20 weight parts, per one weight partof the quinolinecarbaldehyde derivative (starting compound).

The reaction can be carried out by reacting the quinolinecarbaldehydederivative and acetonitrile at an atmospheric pressure or an increasedpressure in an organic solvent in the presence of a base. The reactiontemperature is in the range of preferably 30 to 140° C., more preferably40 to 120° C.

In the reaction utilizing an organic solvent, the base is employed in anamount of preferably 0.5 to 3.0 moles, more preferably 0.8 to 2.0 moles,per one mole of the quinolinecarbaldehyde derivative. (startingcompound).

In the reaction utilizing an organic solvent, acetonitrile is employedin an amount of preferably 0.9 to 50 moles, more preferably 1.0 to 30moles, per one mole of the quinolinecarbaldehyde derivative (startingcompound). The reaction product (desired product) of the reactions ofthe invention, that is, quinolylacrylonitrile derivative can be isolatedand purified after the reaction is complete, by a conventional proceduresuch as recrystallization or column chromatography.

EXAMPLE 1 Preparation of3-[2-Cyclopropyl-4-(4-fluoro-phenyl)-3-quinolyl]prop-2-enenitrile

In a 100 mL-volume glass flask equipped with a stirrer, a thermometerand a dropping funnel were placed under argon atmosphere 1.94 g (6.66mmol) of 2-cyclo-propyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde, 10mL of acetonitrile and 0.422 g (10.6 mmol). of sodium hydride (purity:60%). The content was stirred at room temperature for 2 hours. Theresulting mixture was chilled to −10° C. To the chilled mixture wasadded 20 mL (248 mmol) of ethyl formate, and the mixture was stirred for4 hours at the same temperature. Subsequently, to the mixture was slowlyadded 11 mL of hydrochloric acid (1 mol/L) which was previously chilledin an ice bath. In the mixture, an organic portion separated from anaqueous portion. The organic portion was taken out, washed with two 10mL portions of saturated aqueous sodium chloride solution, and driedover anhydrous magnesium sulfate. The organic portion was filtered andanalyzed by high performance liquid chromatography (absolutequantitative analysis). It was confirmed that 1.71 g (yield: 85%) of3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile wasproduced. The organic portion was concentrated under reduced pressure toleave a yellow solid residue. The solid residue was recrystallized fromtoluene/hexane (1/8, vol. ratio) to obtain 1.79 g of3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile as ayellow crystalline product (purity: 97%). The obtained3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile had thefollowing characteristics:

m.p.: 174.5-175.0° C.; EI-MS(m/e): 314(M), CI-MS(m/e): 315(M+1); IR(KBr, cm⁻¹): 2223, 1513, 1490, 1224, 1161, 846, 768. Elementaryanalysis: C 80.31%, H 4.74%, N 8.89%. (theoretical value for C₂₁H₁₅N₂F:C, 80.24%, H, 4.81%, N, 8.91%) ¹H-NMR (CDCl₃, δ(ppm)): 1.06-1.15 (2H,m), 1.36-1.46 (2H, m), 2.23-2.33 (1H, m), 5.29 (1H, d, J=17.0 Hz),7.18-7.32 (4H, m), 7.34-7.39 (1H, m), 7.52 (1H, d, J=17.0 Hz), 7.60-7.73(1H, m), 7.97 (1H, d, J=8.3 Hz).

EXAMPLE 2 Preparation of3-[2-Cyclopropyl-4-(4-fluoro-phenyl)-3-quinolyl]prop-2-enenitrile

In a flask similar to that employed in Example 1 were placed under argonatmosphere 1.96 g (6.73 mmol) of2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde, 10 mL ofacetonitrile and 0.434 g (10.9 mmol) of sodium hydride (purity: 60%).The content was stirred at room temperature for 2 hours. The resultingmixture was chilled to 0° C. To the chilled mixture was added 0.85 mL(10.5 mmol) of ethyl formate, and the mixture was stirred for 4 hours atthe same temperature. Subsequently, to the mixture was slowly added 10mL of chilled water. The mixture was then extracted with 30 mL of ethylacetate which was previously chilled in an ice bath. The organic portionwas dried over anhydrous magnesium sulfate, and filtered. The filtratewas analyzed by high performance liquid chromatography (absolutequantitative analysis). It was confirmed that 1.74 g (yield: 82%) of3-[2-cyclo-propyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile wasproduced.

EXAMPLE 3 Preparation of3-[2-Cyclopropyl-4-(4-fluoro-phenyl)-3-quinolyl]prop-2-enenitrile

In a 50 ml-volume glass flask equipped with a stirrer and a thermometerwere placed under argon atmosphere 200 mg (0.69 mmol) of2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde, 2 mL ofacetonitrile and 41.5 mg (1.04 mmol) of sodium hydride (purity: 60%).The content was stirred at room temperature for 2 hours. The resultingmixture was chilled to 0° C. To the chilled mixture were added 0.08 mL(1.03 mmol) of methanesulfonyl chloride and 0.15 mL (1.08 mmol) oftriethylamine, and the mixture was stirred for 3 hours at the sametemperature. Subsequently, to the mixture was added 5 mL of chilledwater, and the mixture was extracted with three portions of ethylacetate (15 mL) which were previously chilled in an ice bath. Themixture was dried over anhydrous magnesium sulfate. The organic portionwas then filtered, and the filtrate was analyzed by high performanceliquid chromatography (absolute quantitative analysis). It was confirmedthat 180 mg (yield: 83%) of3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile wasproduced.

EXAMPLE 4 Preparation of3-[2-Cyclopropyl-4-(4-fluoro-phenyl)quinolin-3-yl]-3-hydroxypropionitrile

In a 50 mL-volume glass flask equipped with a stirrer and a thermometerwere placed under argon atmosphere 0.20 g (0.68 mmol) of2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde, 2 mL ofacetonitrile and 0.042 g (1.06 mmol) of sodium hydride (purity: 60w).The content was stirred at room temperature for 2 hours. The resultingmixture was chilled to 0° C. To the chilled mixture was added 0.08 mL(1.40 mmol) of acetic acid, and the mixture was stirred for 5 minutes atthe same temperature. Subsequently, to the mixture was added 10 mL ofchilled water, and the mixture was extracted with 20 mL of ethyl acetatewhich were previously chilled in an ice bath. The organic portion waswashed successively with 5 mL of saturated aqueous sodium hydrogencarbonate solution and 5 mL of saturated aqueous sodium chloridesolution, and dried over anhydrous magnesium sulfate. The organicportion was then filtered and concentrated under reduced pressure. Theconcentrate was purified by silica gel column chromatography [columnWakogel C-200, available from Wako Junyaku Co., Ltd., eluent: ethylacetate/hexane (7/93→15/85, vol. ratio)] to give 0.17 g (yield 75%) of3-[2-cyclopropyl-4-(4-fluoro-phenyl)quinolin-3-yl]-3-hydroxypropionitrileas white solid.

The obtained3-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-3-hydroxypropionitrilehad the following characteristics:

m.p.: 200° C.; EI-MS(m/e): 332(M), CI-MS(m/e): 333(M+1); IR (KBr, cm⁻¹):3496, 2253, 1512, 1491, 1226, 1078, 778. Elementary analysis: C, 75.90%,H, 5.17%, N, 8.39% (theoretical value for C₂₁H₁₇N₂OF: C, 75.89%, H,5.16%, N, 8.43%), ¹H-NMR (CDCl₃, δ(ppm)): 1.07-1.17 (3H, m), 1.79-1.84(1H, m), 2.48 (1H, d, J=4.2 Hz), 2.87-2.96 (1H, m), 3.01 (1H, dd, J=6.6,16.9 Hz), 3.26 (1H, dd, J=8.6, 16.9 Hz), 5.25-5.35 (1H, m), 7.12-7.36(6H, m), 7.63 (1H, m), 7.94 (1H, d, J=8.6 Hz). ¹H-NMR (CDCl₃, δ(ppm)):1.07-1.20 (3H, m), 1.76-1.84 (1H, m), 2.87-2.96 (1H, m), 3.00 (1H, dd,J=6.6, 16.9 Hz), 3.26 (1H, dd, J=8.6, 16.9 Hz), 5.27 (1H, dd, J=6.6, 8.6Hz), 7.11-7.36 (6H, m), 7.64 (1H, m), 7.94 (1H, d, J=9.0Hz).

Reference Example 1 Preparation of3-[2-Cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enal

In a 5 mL-volume glass flask equipped with a stirrer, a thermometer anda dropping funnel were placed under nitrogen atmosphere 314 mg (1.0mmol) of3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile(prepared in Example 1), 2.25 mL of formic acid (60 mmol, mol calculatedas 100% formic acid), 0.75 mL of water, and 620 mg (5.3 mmol as nickelatom) of water-containing developed Raney-nickel (NDHT-90, nickelcontent 50 wt. %, available from Kawaken Fine Chemical Co., Ltd.). Thecontent was reacted at 80° C. for 1.5 hours. After the reaction wascomplete, the content was cooled to room temperature. After addition of9 mL of water and 9 mL of hydrochloric acid (1 mol/L), the catalyst wasremoved by filtration using a celite. The celite was washed with twoportions of 2-butanol (1 mL) and two portions of toluene (9 mL). Theorganic portion was dried over anhydrous magnesium sulfate. The driedorganic portion was filtered and the filtrate was concentrated underreduced pressure to give 307 mg (yield 91%) of3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enal as yellowsolid (purity 97%, in terms of an area percent according to highperformance liquid chromatography).

The obtained 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enalhad the following characteristics:

CI-MS(m/e): 318(M+1); ¹H-NMR (CDCl₃, δ(ppm)): 1.07-1.13 (2H, m),1.40-1.45 (2H, m), 2.32-2.37 (1H, m), 6.43 (1H, dd, J=7.8, 16.2 Hz),7.22-7.26 (4H, m), 7.35-7.38 (2H, m), 7.55 (1H, d, J=16.2 Hz),7.644-7.69 (1H, m), 7.97 (1H, d, J=8.4 Hz), 9.51 (1H, d, J=7.5 Hz).

EXAMPLE 5 Preparation of3-[2-cyclopropyl-4-(4-fluoro-phenyl)-3-quinolyl]prop-2-enenitrile

In a 200 mL-volume glass flask equipped with a stirrer and a thermometerwere placed under argon atmosphere 9.2 g (31.6 mmol) of2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde, 7.5 mL (143mmol) of acetonitrile, 45 mL of toluene (dielectric constant at 25° C.:2.38), and 1.99 g (36.8 mmol) of sodium methoxide. The content wasreacted at 50° C. for 8 hours. The resulting mixture was chilled in anice bath. To the chilled mixture were slowly added under stirring 40 mLof toluene and 34.0 mL (34.0 mmol) of hydrochloric acid (1 mol/L),successively. The separated organic portion was taken out. After washingwith 30 mL of saturated aqueous sodium chloride solution, the organicportion was dried over anhydrous magnesium sulfate. The organic portionwas then filtered and analyzed by high performance liquid chromatography(absolute quantitative analysis). It was confirmed that 9.52 g (yield:96%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrilewas produced. The organic portion was concentrated under reducedpressure, and the residue was crystallized from ethyl acetate/hexane(15/85, vol. ratio) to obtain 9.29 g (yield 88%) of3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile as ayellow crystalline product (purity: 94%, measured by high performanceliquid chromatography).

The obtained3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile hadalmost the same characteristics as those described in Example 1.

EXAMPLE 6 Preparation of3-[2-Cyclopropyl-4-(4-fluoro-phenyl)-3-quinolyl]prop-2-enenitrile

In a 50 mL-volume glass flask equipped with a stirrer and a thermometerwere placed under argon atmosphere 1.75 g (6.01 mmol) of2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde, 2.5 mL (47.5mmol) of acetonitrile, 13.5 mL of methylal (dielectric constant at 20°C.: 2.7), and 0.56 g (10.3 mmol) of sodium methoxide. The content wasreacted at 41° C. for 9 hours. The resulting mixture was chilled in anice bath. To the chilled mixture were slowly added under stirring 30 mLof toluene and 7.0 mL (7.00 mmol) of hydrochloric acid (1 mol/L),successively. The separated organic portion was taken out. After washingwith two portions of saturated aqueous sodium chloride solution (10 mL),the organic portion was dried over anhydrous magnesium sulfate. Theorganic portion was then filtered and analyzed by high performanceliquid chromatography (absolute quantitative analysis). It was confirmedthat 1.79 g (yield: 96%) of3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile wasproduced.

EXAMPLE 7 Preparation of3-[2-Cyclopropyl-4-(4-fluoro-phenyl)-3-quinolyl]prop-2-enenitrile

In a flask similar to that of Example 6 were placed under argonatmosphere 1.74 g (5.98 mmol) of2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde, 0.80 mL (15.2mmol) of acetonitrile, 8.0 mL of tetrahydrofuran (dielectric constant at25° C.: 7.58), and 0.41 g (7.55 mmol) of sodium methoxide. The contentwas reacted at 52° C. for 4.5 hours. The resulting mixture was chilledin an ice bath. To the chilled mixture were slowly added under stirring30 mL of toluene and 7.0 mL (7.00 mmol) of hydrochloric acid (1 mol/L),successively. The separated organic portion was taken out. After washingwith two portions of saturated aqueous sodium chloride solution (10 mL),the organic portion was dried over anhydrous magnesium sulfate. Theorganic portion was then filtered and analyzed by high performanceliquid chromatography (absolute quantitative analysis). It was confirmedthat 1.64 g (yield: 88%) of3-[2-cyclopropyl-4-(4-fluoro-phenyl)-3-quinolyl]prop-2-enenitrile wasproduced.

INDUSTRIAL APPLICABILITY

According to the preparation method of the invention, the known3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile isproduced from a known quinolinecarbaldehyde derivative in a simpleprocedure. The quinolylacrylonitrile derivative can be effectivelyutilized to the known quinolylpropenal derivative.

What is claimed is:
 1. A process for preparing 3-(2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl) prop-2-enenitrile which comprises the steps of: reacting 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde with acetonitrile in the presence of a base to produce a mixture of 3-(2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl) prop-2-enenitrile and 3-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3-hydroxy-propionitrile; and dehydrating the mixture in the presence of a dehydrating agent.
 2. The process of claim 1, wherein the base is employed in an amount of 0.9 to 3.0 moles per one mole of the carbaldehyde.
 3. The process of claim 1, wherein the base is a metal hydride, a metal amide, a metal alkoxide, an alkyl lithium, or a metal hydroxide.
 4. The process of claim 1, wherein the base is sodium hydride, potassium hydride, calcium hydride, or sodium methoxide.
 5. The process of claim 1, wherein the acetonitrile is employed in an amount of 0.9 to 100 moles per one mole of the carbaldehyde.
 6. The process of claim 1, wherein the dehydrating agent is an inorganic acid, an organic acid, an organic acid ester, an amide, an organic acid anhydride, an acid chloride, a tertiary amine, or a silane compound.
 7. The process of claim 1, wherein the dehydrating agent is a formic acid ester.
 8. 3-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3-hydroxypropionitrile.
 9. A process for preparing 3-(2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl) prop-2-enenitrile which comprises the steps of: reacting 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde with acetonitrile in the presence of a base; and dehydrating the resulting product in the presence of a dehydrating agent.
 10. The process of claim 9, wherein the base is employed in an amount of 0.9 to 3.0 moles per one mole of the carbaldehyde.
 11. The process of claim 9, wherein the base is a metal hydride, a metal amide, a metal alkoxide, an alkyl lithium, or a metal hydroxide.
 12. The process of claim 9, wherein the base is sodium hydride, potassium hydride, calcium hydride, or sodium methoxide.
 13. The process of claim 9, wherein the acetonitrile is employed in an amount of 0.9 to 100 moles per one mole of the carbaldehyde.
 14. The process of claim 9, wherein the dehydrating agent is an inorganic acid, an organic acid, an organic acid ester, an amide, an organic acid anhydride, an acid chloride, a tertiary amine, or a silane compound.
 15. The process of claim 9, wherein the dehydrating agent is a formic acid ester.
 16. A method for preparing 3-(2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl) prop-2-enenitrile which comprises reacting 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde with acetonitrile in an organic solvent in the presence of a base.
 17. The method of claim 16, wherein the organic solvent has a dielectric constant of 10 or less in the temperature range of 20 to 25° C.
 18. The method of claim 17, wherein the organic solvent having a dielectric constant of 10 or less in the temperature range of 20 to 25° C. is an aromatic solvent or ether solvent.
 19. The method of claim 16, wherein the base is an alkoxide of an alkali metal or an alkaline earth metal.
 20. The method of claim 16, wherein the reaction is performed in the temperature range of 40 to 120° C. 